Mapping the neuronal circuitry underlying indirect striatal to hypothalamic connectivity and its role in feeding

绘制间接纹状体与下丘脑连接的神经元回路及其在进食中的作用

• 批准号: 10491244
• 负责人: Miriam E. Bocarsly
• 金额: $ 24.9万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491244
• 关键词: Address; Automobile Driving; Autopsy; Behavior; Behavioral; Brain region; Cells; Complex; Corpus striatum structure; Data; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Eating; Energy Intake; Feeding behaviors; Food Intake Regulation; Globus Pallidus; Glutamates; Hypothalamic structure; LH Cell; Lateral; Lesion; Link; Literature; Maps; Mediating; Methods; Motivation; Neurons; Nucleus Accumbens; Obesity; Pathway interactions; Pharmacology; Phenotype; Population; Positioning Attribute; Regulation; Research; Rewards; Role; Synapses; Techniques; Testing; Tissues; Training; Transgenic Mice; Ventral Striatum; Viral; behavioral study; brain pathway; career; cell type; designer receptors exclusively activated by designer drugs; energy balance; experience; feeding; food consumption; gamma-Aminobutyric Acid; hedonic; hypocretin; melanin-concentrating hormone; nerve supply; neuronal circuitry

Food consumption is fundamental to species survival and understanding the neuronal circuitry underlying feeding behaviors is of the utmost importance. Amassing evidence supports the idea that control of caloric intake is complex and involves calculations of hedonic value, reward and motivation. Thus, it requires interactions between brain regions classically implemented in feeding (such as the lateral hypothalamus; LH) and the regions modulating reward (such as the ventral striatum). While the intersection of these regions has been suggested, the cell-type specific circuitry linking these pathways is poorly understood. The objective of this proposal is to further elucidate the cell-type specific circuitry underlying striatal-to-lateral hypothalamic connections and determine its role in feeding, while gaining training in new neuronal circuitry mapping techniques. There is evidence that the striatum exerts its control over feeding behaviors by interfacing with the LH. Previous research indicates that the ventral striatum, and specifically the nucleus accumbens shell (NAcS), and the LH are connected via a direct pathway. However, rudimentary tracing and behavioral studies have suggested a second, indirect pathway, with the NAcS projecting to the ventral pallidum (VP), which in turn projects to the LH. However, despite this initial evidence, cell-type specific, neuronal circuitry in this indirect pathway remains unknown. Using viral tracing methods and chemogenetic approaches I will determine the cell-types implicated in each component of this three-part circuitry, and how they mediate feeding behaviors. I hypothesize that GABAergic striatal projection neurons expressing the dopamine D2 receptor in the NAcS preferentially innervate GABAergic cells in the VP, which in turn disinhibit LH GABA neurons to facilitate feeding. Furthermore, in understanding the brain pathways and connectivity underlying food intake behaviors, this project will ultimately allow us to better understand perturbations that occur in disease states such as obesity.

食物摄取是物种生存和了解其背后的神经回路的基础 摄食行为是最重要的。越来越多的证据支持这样一种观点：控制卡路里 摄取是复杂的，涉及享乐价值、奖励和动机的计算。因此，它需要 大脑中典型的摄食区域之间的相互作用(如下丘脑外侧核；黄体生成素) 以及调节奖赏的区域(如腹侧纹状体)。虽然这些区域的交集已经 有人提出，连接这些通路的细胞类型特定电路知之甚少。的目标是 这一建议是为了进一步阐明纹状体到外侧下丘脑的细胞型特定回路。 并确定其在进食中的作用，同时接受新的神经元回路映射方面的培训 技巧。 有证据表明，纹状体通过与黄体生成素的相互作用来控制取食行为。 先前的研究表明，腹侧纹状体，特别是伏隔核壳(NaCs)， 和黄体生成素是通过直接途径连接的。然而，初步的追踪和行为研究 提出了第二种间接通路，NAC投射到腹侧苍白球(VP)，而腹侧苍白球 将项目提交给左撇子。然而，尽管有这一初步证据，但细胞类型特定的、神经元回路在这种间接 途径仍不清楚。使用病毒追踪方法和化学遗传学方法，我将确定 在这个三部分电路的每个组件中所涉及的细胞类型，以及它们如何调节摄食行为。我 NACS中表达多巴胺D2受体的GABA能纹状体投射神经元的假说 优先支配VP内的GABA能细胞，进而抑制LHGABA能神经元的易化 喂食。 此外，在理解大脑通路和食物摄入行为背后的连接时，这一点 该项目最终将使我们能够更好地了解肥胖等疾病状态下发生的扰动。